Pathway Enrichment
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2021 ◽  
Vol 11 (1) ◽  
Xincheng Wu ◽  
Zhengping Bai

AbstractEpigenetic modifications, especially N6-methyladenosine (m6A) modification, play a key role in tumor microenvironment (TME) infiltration. However, the regulatory role of m6A modification in the TME of lung adenocarcinoma (LUAD) remains unclear. A total of 2506 patients with LUAD were included in the analysis and divided into different groups according to distinct m6A modification-related patterns based on 23 m6A regulators. A comprehensive analysis was performed to explore TME infiltration in different m6A modification-related patterns. Principal component analysis was performed to obtain the m6Ascore and to quantify m6A modification-related patterns in different individuals. Three distinct m6A modification-related patterns were identified by 23 m6A regulators. The pathway enrichment analysis showed that m6Acluster-A was associated with immune activation; m6Acluster-B was associated with carcinogenic activation; m6Acluster-C was prominently related to substance metabolism. M6Acluster-A was remarkably rich in TME-infiltrating immune cells and patients with this pattern showed a survival advantage. The m6Ascore could predict TME infiltration, tumor mutation burden (TMB), the effect of tumor immunotherapy, and the prognosis of patients in LUAD. High m6Ascore was characterized by increased TME infiltration, reduced TMB, and survival advantage. Patients with a high m6Ascore exhibited significantly improved clinical response to anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA4) immunotherapy. This study explored the regulatory mechanisms of TME infiltration in LUAD. The comprehensive analysis of m6A modification-related patterns may contribute to the development of individualized immunotherapy and the improvement of the overall effectiveness of immunotherapy for LUAD patients.

2021 ◽  
Vol 11 (1) ◽  
Dankun Luo ◽  
Wenchao Yao ◽  
Qiang Wang ◽  
Qiu Yang ◽  
Xuxu Liu ◽  

AbstractLong non-coding RNA (lncRNA) is a prognostic biomarker for many types of cancer. Here, we aimed to study the prognostic value of lncRNA in Breast Invasive Carcinoma (BRCA). We downloaded expression profiles from The Cancer Genome Atlas (TCGA) datasets. Subsequently, we screened the differentially expressed genes between normal tissues and tumor tissues. Univariate Cox, LASSO regression, and multivariate Cox regression analysis were used to construct a lncRNA prognostic model. Finally, a nomogram based on the lncRNAs model was developed, and weighted gene co-expression network analysis (WGCNA) was used to predict mRNAs related to the model, and to perform function and pathway enrichment. We constructed a 6-lncRNA prognostic model. Univariate and multivariate Cox regression analysis showed that the 6-lncRNA model could be used as an independent prognostic factor for BRCA patients. We developed a nomogram based on the lncRNAs model and age, and showed good performance in predicting the survival rates of BRCA patients. Also, functional pathway enrichment analysis showed that genes related to the model were enriched in cell cycle-related pathways. Tumor immune infiltration analysis showed that the types of immune cells and their expression levels in the high-risk group were significantly different from those in the low-risk group. In general, the 6-lncRNA prognostic model and nomogram could be used as a practical and reliable prognostic tool for invasive breast cancer.

2021 ◽  
Wensen Jiang ◽  
Juliane Dagmar Glaeser ◽  
Khosrowdad Salehi ◽  
Giselle Kaneda ◽  
Pranav Mathkar ◽  

The origin, composition, distribution, and function of cells in the human intervertebral disc (IVD) has not been fully understood. Here, cell atlases of both human neonatal and adult IVDs have been generated and further assessed by gene ontology pathway enrichment, pseudo-time trajectory, histology, and immunofluorescence. Comparison of cell atlases revealed the presence of several sub-populations of notochordal cells (NC) in the neonatal IVD and a small quantity of NCs and associated markers in the adult IVD. Developmental trajectories predicted that most neonatal NCs develop into adult nucleus pulposus cells (NPCs) while some keep their identity throughout adulthood. A high heterogeneity and gradual transition of annulus fibrosus cells (AFCs) in the neonatal IVD was detected and their potential relevance in IVD development was assessed. Collectively, comparing single-cell atlases between neonatal and adult IVDs delineates the landscape of IVD cell biology and may help discover novel therapeutic targets for IVD degeneration.

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258316
Paul A. Wilson ◽  
Sara Santos Franco ◽  
Liu He ◽  
Nicholas W. Galwey ◽  
Jackie Meakin ◽  

RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the treatment of several autoimmune diseases. Human genetic studies indicate a significant contributory role for RORC in several human disease conditions. Furthermore, genome-wide association studies (GWAS) report a significant association between inflammatory bowel disease (IBD) and the RORC regulatory variant rs4845604. To investigate if the rs4845604 variant may affect CD4+ T cell differentiation events, naïve CD4+ T cells were isolated from eighteen healthy subjects homozygous for the rs4845604 minor (A) or major (G) allele). Isolated cells from each subject were differentiated into distinct T cell lineages by culturing in either T cell maintenance medium or Th17 driving medium conditions for six days in the presence of an RORC inverse agonist (to prevent constitutive receptor activity) or an inactive diastereomer (control). Our proof of concept study indicated that genotype had no significant effect on the mean number of naïve CD4 T cells isolated, nor the frequency of Th1-like and Th17-like cells following six days of culture in any of the four culture conditions. Analysis of the derived RNA-seq count data identified genotype-driven transcriptional effects in each of the four culture conditions. Subsequent pathway enrichment analysis of these profiles reported perturbation of metabolic signalling networks, with the potential to affect the cellular detoxification response. This investigation reveals that rs4845604 genotype is associated with transcriptional effects in CD4+ T cells that may perturb immune and metabolic pathways. Most significantly, the rs4845604 GG, IBD risk associated, genotype may be associated with a differential detoxification response. This observation justifies further investigation in a larger cohort of both healthy and IBD-affected individuals.

2021 ◽  
Vol 11 (1) ◽  
Xiaoyu Zeng ◽  
Gaoli Shi ◽  
Qiankun He ◽  
Pingping Zhu

AbstractBreast cancer is the most common cancer and the leading cause of cancer-related deaths in women. Increasing molecular targets have been discovered for breast cancer prognosis and therapy. However, there is still an urgent need to identify new biomarkers. Therefore, we evaluated biomarkers that may aid the diagnosis and treatment of breast cancer. We searched three mRNA microarray datasets (GSE134359, GSE31448 and GSE42568) and identified differentially expressed genes (DEGs) by comparing tumor and non-tumor tissues using GEO2R. Functional and pathway enrichment analyses of the DEGs were performed using the DAVID database. The protein–protein interaction (PPI) network was plotted with STRING and visualized using Cytoscape. Module analysis of the PPI network was done using MCODE. The associations between the identified genes and overall survival (OS) were analyzed using an online Kaplan–Meier tool. The redundancy analysis was conducted by DepMap. Finally, we verified the screened HUB gene at the protein level. A total of 268 DEGs were identified, which were mostly enriched in cell division, cell proliferation, and signal transduction. The PPI network comprised 236 nodes and 2132 edges. Two significant modules were identified in the PPI network. Elevated expression of the genes Discs large-associated protein 5 (DLGAP5), aurora kinase A (AURKA), ubiquitin-conjugating enzyme E2 C (UBE2C), ribonucleotide reductase regulatory subunit M2(RRM2), kinesin family member 23(KIF23), kinesin family member 11(KIF11), non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG), ZW10 interactor (ZWINT), and denticleless E3 ubiquitin protein ligase homolog(DTL) are associated with poor OS of breast cancer patients. The enriched functions and pathways included cell cycle, oocyte meiosis and the p53 signaling pathway. The DEGs in breast cancer have the potential to become useful targets for the diagnosis and treatment of breast cancer.

2021 ◽  
Vol 16 (1) ◽  
Zheng-yuan Wu ◽  
Gang Du ◽  
Yi-cai Lin

Abstract Background Osteoarthritis (OA) is the most common chronic degenerative joint disorder globally that is characterized by synovitis, cartilage degeneration, joint space stenosis, and sub-cartilage bone hyperplasia. However, the pathophysiologic mechanisms of OA have not been thoroughly investigated. Methods In this study, we conducted various bioinformatics analyses to identify hub biomarkers and immune infiltration in OA. The gene expression profiles of synovial tissues from 29 healthy controls and 36 OA samples were obtained from the gene expression omnibus database to identify differentially expressed genes (DEGs). The CIBERSORT algorithm was used to explore the association between immune infiltration and arthritis. Results Eighteen hub DEGs were identified as critical biomarkers for OA. Through gene ontology and pathway enrichment analyses, it was found that these DEGs were primarily involved in PI3K-Akt signaling pathway and Rap1 signaling pathway. Furthermore, immune infiltration analysis revealed differences in immune infiltration between patients with OA and healthy controls. The hub gene ZNF160 was closely related to immune cells, especially mast cell activation in OA. Conclusion Overall, this study presented a novel method to identify hub DEGs and their correlation with immune infiltration, which may provide novel insights into the diagnosis and treatment of patients with OA.

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12300
Jingwen Zhou ◽  
Rui Liu ◽  
Min Shuai ◽  
Zhu-Yun Yan ◽  
Xin Chen

Salvia miltiorrhiza (Labiatae) is an important medicinal plant in traditional Chinese medicine. Tanshinones are one of the main active components of S. miltiorrhiza. It has been found that the intraspecific variation of S. miltiorrhiza is relatively large and the content of tanshinones in its roots of different varieties is also relatively different. To investigate the molecular mechanisms that responsible for the differences among these varieties, the tanshinones content was determined and comparative transcriptomics analysis was carried out during the tanshinones accumulation stage. A total of 52,216 unigenes were obtained from the transcriptome by RNA sequencing among which 23,369 genes were differentially expressed among different varieties, and 2,016 genes including 18 diterpenoid biosynthesis-related genes were differentially expressed during the tanshinones accumulation stage. Functional categorization of the differentially expressed genes (DEGs) among these varieties revealed that the pathway related to photosynthesis, oxidative phosphorylation, secondary metabolite biosynthesis, diterpenoid biosynthesis, terpenoid backbone biosynthesis, sesquiterpenoid and triterpenoid biosynthesis are the most differentially regulated processes in these varieties. The six tanshinone components in these varieties showed different dynamic changes in tanshinone accumulation stage. In addition, combined with the analysis of the dynamic changes, 277 DEGs (including one dehydrogenase, three CYP450 and 24 transcription factors belonging to 12 transcription factor families) related to the accumulation of tanshinones components were obtained. Furthermore, the KEGG pathway enrichment analysis of these 277 DEGs suggested that there might be an interconnection between the primary metabolic processes, signaling processes and the accumulation of tanshinones components. This study expands the vision of intraspecific variation and gene regulation mechanism of secondary metabolite biosynthesis pathways in medicinal plants from the “omics” perspective.

2021 ◽  
Vol 11 ◽  
Shang-Ju Tang ◽  
Guo-Rong You ◽  
Joseph T. Chang ◽  
Ann-Joy Cheng

Head and neck cancer (HNC) is one of the most prevalent cancers worldwide, accounting for approximately 5% of all cancers. While the underlying molecules and their pathogenetic mechanisms in HNC have yet to be well elucidated, recent studies have shown that dysregulation of lncRNAs may disrupt the homeostasis of various biological pathways. However, the understanding of lncRNAs in HNC is still limited by the lack of expression profiling. In the present study, we employed a systematic strategy to identify a panel of lncRNA associated with HNC. A cancer-related lncRNA profile PCR array was screened to explore potential molecules specific for HNC. A total of 55 lncRNAs were found to be dysregulated in HNC cells when compared to normal keratinocytes. Further analysis of the prognostic significance using The Cancer Genome Atlas (TCGA) database revealed 15 lncRNAs highly correlated with overall survival in HNC patients. Additionally, clinical sample expression analysis of the TCGA-HNSC cohort revealed 16 highly dysregulated lncRNAs in HNC, resulting in a combined 31-lncRNA signature panel that could predict prognosis. Validation of these molecules confirmed the considerable level of altered expressions in HNC cells, with XIST, HOXA11-AS, TSIX, MALAT1, WT1-AS, and IPW being the most prominently dysregulated. We further selected a molecule from our panel (XIST) to confirm the validity of these lncRNAs in the regulation of cancer aggressiveness. Gene ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses demonstrated that XIST participated in various cancer-related functions, including cell proliferation and metastasis. XIST silencing with the RNAi technique substantially reduced invasion and migration in several HNC cell lines. Thus, our study defined a 31-lncRNA panel as prognostic signatures in HNC. These perspective results provide a knowledge foundation for further application of these molecules in precision medicine.

Vin-Cent Wu ◽  
Kang-Yung Peng ◽  
Yu-Ping Kuo ◽  
Hsuan Liu ◽  
Bertrand Chin-Ming Tan ◽  

There have been no reports of outcome differences between distinctive subgroups in patients with unilateral primary aldosteronism with histopathologically classical adenomas. The characteristics and incidence of complete clinical success in the patients with unilateral primary aldosteronism could be associated with the concomitant existence of multiple aldosterone-producing micronodules/nodules. Altogether, 74 classical adenomas (mean, 52.9 years and 40 men [54.1%]) were identified among 98 operated patients with unilateral primary aldosteronism. Among them accompanying multiple aldosterone-producing micronodules/nodules (group A) were identified in 38 (51.3%) of the adrenal glands; these patients showed lower likelihood (42.1%) to achieve complete clinical success than that (80.6%) of those with aldosterone-producing adenoma/nodules alone (group B, P =0.001). Additionally, group A adenomas were associated with less complete clinical success (odds ratio, 5.53, P =0.005) in the multivariable regression analysis. Group A patients also had higher baseline aldosterone production (absolute aldosterone ratio) from the contralateral adrenal gland ( P =0.039). Based on the patterns of genes with highly differential expressions as uncovered by RNA-seq analysis, Group A adenomas showed distinct transcriptomic profiles in comparison to the gene expressions from Group B adenomas. Pathway enrichment analysis revealed that HTR2B-mediated calcium pathway, in terms of HTR2B , and PLCE1 was prominently downregulated in Group A adenomas. There was 51.3% of the patients with unilateral primary aldosteronism with classical group A adenomas. These patients were more likely to have hypertension-persistence after adrenalectomy. The functional signatures of Group A adenomas showed attenuated HTR2B-mediated PLC/IP3/Ca2 + pathway; this may provide some mechanistic explanation to various clinical outcomes.

2021 ◽  
Angelu Mae A Ferrer ◽  
Janella Rayne A David ◽  
Arvin A Taquiqui ◽  
Arci A Bautista ◽  
Custer C Deocaris ◽  

Breast cancer is considered as one of the three most common cancers around the world and the second leading cause of cancer deaths among women. Coix lachrymal jobi, commonly known as Jobs tears or adlay has been reported to possess anti-cancer properties. Despite evidences provided by clinical data, the usage of Coix lacryma-jobi in treating cancer, particularly breast cancer, has been scarce. Thus, this study was conducted to determine the pharmacological mechanisms underlying its anti-breast cancer property using various network pathway analyses. Bioactive compounds from Coix lacryma-jobi and its potential target genes were obtained from SymMap. Breast cancer-related target genes were collected from CTD. Protein-protein interaction network was analyzed using the STRING database. GO and KEGG pathway enrichment analyses were performed using DAVID to further explore the mechanisms of Coix lacryma-jobi in treating breast cancer. PPI and compound-target-pathway were visualized using Cytoscape. A total of 26 bioactive compounds, 201 corresponding targets, 36625 breast cancer-associated targets were obtained, and 200 common targets were considered potential therapeutic targets. The 9 bioactive compounds identified were berberine, oleic acid, beta-sitosterol, sitosterol, linoleic acid, berberrubine, jatrorrhizine, thalifendine, and stigmasterol. The identified 5 core targets were ESR1, JUN, MAPK14, and RXRA. Coix lacryma-jobi targets enriched in GO terms were mostly involved in regulation of transcription from RNA polymerase II promoter, drug response, steroid hormone receptor activity, and protein binding. This study elucidates on the pharmacological underpinnings on the potency of adlay against breast cancer. Its subsequent drug development will be worth a step forward for a breast cancer-free society.

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